New oxabicyclononanes

ABSTRACT

Compounds of the formula   WHEREIN Z4 represents a free, esterified or etherified hydroxy group, are produced by solvolysing 4 Beta -amino-9,10dioxatricyclo (4,3,1,03,8)decan-5 Alpha -ol; they are intermediates in the synthesis of prostaglandins.

United States Patent 11 1 Woodward 51 Oct. 21, 1975 l NEW OXABICYCLONONANES [75] Inventor: Robert Burns Woodward,

Cambridge, Mass.

[73] Assignee: Ciba-Geigy Corporation, Ardsley,

22 1 Filed: Feb. 2, 1973 21 Appl. No.: 329,249

[30] Foreign Application Priority Data OTHER PUBLICATIONS Corey et al., Tetrahedron Letters, No. 4, pp. 31 1-313, 1970.

Primary Examiner-G. Thomas Todd Attorney, Agent, or Firm.loseph G. Kolodny; John J. Maitner; Theodore O. Groeger [57] ABSTRACT Compounds of the formula no "on wherein 2,, represents a free, esterified or etherified hydroxy group, are produced by solvolysing 4B-amino-9. l O-dioxatricyclo [4,3, l ,0 -]decan-5 a-ol; they are intermediates in the synthesis of prostaglandins.

7 Claims, No Drawings NEW OXABICYCLONONANES The present invention relates to new oxabicyclononane derivatives and to a process for their manufacture. The new compounds are valuable intermediate products for the manufacture of highly potent prostaglandins by a new, sterically controlled method process.

The invention relates in particular to new 7- oxabicyclo [4,3,0]nonane derivatives of the formula VIII wherein Z. represents a free, etherified or esterified hydroxy group, the optical antipodes and racemates thereof and acid addition salts thereof, and to a method process for their manufacture.

The significance of the present invention resides in the manufacture from readily accessible and inexpensive starting materials of intermediate products which an be used for the stereospecific synthesis both of known, naturally occurring prostaglandins as Well as of new synthetic prostaglandins. The individual steps proceed with high yields. The new intermediate products are therefore suitable for carrying out the synthesis of the cited prostaglandins on an industrial scale.

From these intermediate products it is possible to manufacture first and foremost the prostaglandins of the F -series which are characterised by an optionally unsaturated a-alkanecarboxylic acid in 8-position, an a-hydroxyolefine grouping in l2-position and two a-hydroxy groups in 9,1 l-position. Secondly, it is possible to use the new compounds as intermediate products for the manufacture of prostaglandins of the E, A and B series, and furthermore of derivatives and homologs of prostaglandins.

The biological activity and the importance of prostaglandins in medicine are known and described, for example, by M. P. L. Caton in Progr. Med. Chem. 8, 317 (1971 The standard prostaglandin numbering used herein is derived from prostanoic acid which has the following structure:

In the above formulae, as well as in those hereinafter, dotted lines indicate substituents which are situated behind the plane defined by the cyclopentane ring; these substituents are denoted by 01. Thickly drawn lines indicate substituents which are in front of this plane; these are denoted by 8. Substituents linked by wavy lines can be in the aor ,B-configuration. The standard prostaglandin nomenclature is used as illustrated hereinabove in the formula of prostanoic acid. For the standard prostaglandin nomenclature compare also 8.. Bergstrom, Science, 157, 382 (1967), M. P. L. Caton, Progr. Med. Chem. 8, 317, 1971) and Niels Andersen, Annals of the New York Academy of Sciences, Vol. 180, S. 14, Apr. 30, 1971.

The stereospecific manufacture of the cited prostaglandins using the new compounds according to the invention is carried out by a new and original multi-step process. The following scheme reproduces, for example, the synthesis of natural prostaglandins F (PGF (Xllla) and P (PGF (Xlllb). Synthesis scheme DH @01 0): Gl nn):

n R R r on 5 2 HH H in the formulae Xb, XIb, XIIb and XIIIb, R represents the group and in the formula Xc, R represents the group In the above scheme, only those compounds which lead to the naturally occurring prostaglandins F and P have been specified. The optical antipodes and diasteroisomers which occur in the reactions, and their separation, will be dealt with in what follows hereinafter.

The individual reaction steps are described briefly below, but no limitation to these reaction conditions and to the specifically cited reagents is to be deduced therefrom.

1st. Step Cis-cyclohexane-1,3,5-triol [KI-I. Steinacker and H. Stetter, Chem. Ber. 85, 451 (1952)] is converted with glyoxylic acid, or a reactive functional derivative thereof, e.g. its hydrate, an ester or an acetal, into the compound of the formula I, in which X and X together represent the oxo group. The reaction is advantageously carried out in the presence of an acid catalyst, e.g. p-toluenesulphonic acid, in an inert solvent, e.g. benzene or ethylene glycol dimethyl ether, at a temperature of about C to the boiling point of the solvent employed.

The compound of the formula I, in which X represents a hydrogen atom and X represents the hydroxy group, is formed when cis-cyclohexane-1,3,5-triol is reacted under similar conditions with glyoxal, or a reactive functional derivative thereof, e.g. the hydrate or one of its acetals.

2nd. Step A compound of the formula I is converted by reduction into a compound of the formula II, wherein Z and Z are hydroxy groups. Complex hydrodes, e.g. lithium aluminium hydride, lithium borohydride or sodium borohydride, can be used as reducing agents. The reduction is carried out at reduced or slightly elevated temperature, preferaby between about 10C and 100C. in a suitable solvent. Lithium aluminium hydride or lithium borohydride are preferably used in ethereal liquids, such as diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran or dioxan. It is also possible to carry out the reduction with sodium borohydride in lower alkanols,

such as methanol, ethanol, isopropanol or tert. butanol, or also in water.

3rd. Step The compound falling under the formula II manufactured in the 2nd. step, in which Z and Z are hydroxy groups, is converted with methanesulphonyl chloride and pyridine into its dimesylate, which also falls under the formula II. The reaction can be carried out in pyridine as solvent and maintaining low temperatures, about 20C, According to another esterification method, it is possible to use triethylamine as proton acceptor and methylene chloride as solvent.

4th. Step The compound of the formula II, wherein Z and Z represent esterified hydroxy groups, e.g. mesyloxy groups, is converted into the compound of the formula III, in which Z has the same meaning as in the starting material, by splitting off I-I-Z with a base to form the double bond. Organic or inorganic bases can be used as bases. Particularly suitable bases are 1,5- diazabicylco [5,4,0]undec-5-ene, which can be used in e.g. dimethyl sulphoxide at a temperature of about 110C, or tetra-n-butylammonium fluoride, which can be used e.g. in dimethyl formamide at a temperature of about 60C. Particularly preferred are alkali hydroxides, such as potassium hydroxide, e.g. in lower alkanols, such as isopropanol, at elevated, e.g. reflux, temperature.

In the reaction according to this step the reacemate is formed, which can be used as such in the next step. If desired, the racemate can be resolved into both its optical antipodes by one of the methods described hereinafter.

5th. Step The bicyclic compound of the formula III, wherein Z is for example a mesyloxy group, or the corresponding racemate, can be converted in surprising manner into the tricyclic compound of the formula IV, wherein Z is a hydroxy group. This reaction is surprising because normally the formation of two six-membered rings, but not of a five-membered and a seven-membered ring, would be expected.

The reaction is preferably carried out in a watermiscible solvent, e.g. in ethylene glycol dimethyl ether/water mixture, in the presence of potassium carbonate at a temperature of about C.

If a start is made from the racemit mixture, consisting of the compound of the formula III and its optical antipode, there is obtained the racemit mixture consisting of the compound of the formula IV and its optical antipodes. The separation into the antipodes can also be effected in this step as described further on. However, instead of starting from the racemate, it is also possible to start from the optically active compound of the formula III, in the process of which the optically active compound of the formula IV is obtained directly.

6th. Step The secondary alcohol of the formula IV, wherein Z is a hydroxy group, or its racemate, is converted in the usual manner with methanesulphonyl chloride and a suitable base, e.g. triethylamine or pyridine, in a suitable solvent, e.g. in methylene chloride, into the compound of the formula IV, in which Z represents the mesyloxy group. If desired, it is also possible in this step to effect the resolution into the optical antipodes, as described later in more detail.

7th. Step The methylsulphonyl ester of the formula IV, or its racemate, is converted into the unsaturated compound of the formula V, or its racemate, by splitting off methanesulphonic acid. The splitting off is effected in the presence of a base, e.g. potassium tert. butylate, or 1,5- diazabicyclo [5,4,0]undec-5-ene, in a solvent, e.g. dimethyl'sulphoxide, or, preferably in the presence of an alkali hydroxide, such as potassium hydroxide, in a boiling lower alkanol, such as isopropanol.

8th. Step The unsaturated compound of the formula V, or 'its racemate, is oxidised with e.g. a hydroperoxide, for example, a peracid, such as m-chloroperbenzoic acid, or, preferably, with a peroxyimidic acid, for example peroxybenzimidic acid, to a mixture consisting of the a-epoxide of the formula VI and the corresponding B-epoxide, or the racemates .thereof, preferably at slightly elevated temperature or elevated temperature, e.g. between about 0C and 50C. When using a peracid, such as m-chloroperbenzoic acid, the B-epoxide is formed as main product; when using a peroxyimidic acid, such as peroxybenzimidic acid, which can be prepared from an optionally substituted benzonitrile or lower alkyl nitrile with hydrogen peroxide in the pres ence of a base, such as an alkali metal bicarbonate, e.g. potassium bicarbonate, in a solvent, such as a lower alkanol e.g. .in methanol, surprisingly more 01- than B-epoxide is obtained. Both epoxides can be separated, for example, by chromatography, or further processed as a mixture. The separated ,B-epoxide, or its racemate, can be reduced with a complex hydride, e.g. with lithium aluminum hydride, in a solvent, e.g. in tetrahydrofuran, to an alcohol of the formula IV, or its racemate. The B-epoxide is thereby led back into the process. In this step it is also possible to perform any desired racemate separation.

9th. Step In an a-epoxide of the formula VI, or its racemate, it is possible to open the expoxide ring, for example, with ammonia in a solvent, such as water, at elevated temperature, e.g. between about 50C and 150C, optionally under pressure, in the process of which a compound of the formula VII, its racemate or acid addition salts thereof, are formed. The epoxide ring is opened in such a way that the 4 amino-Sa-hydroxy compound of the formula VII, or its racemate, is formed. The possible isomeric 5,8-amino-4a-hydroxy compound is not obtained, or is obtained in undetectably small amounts. If desired, it is possible to resolve an optionally resulting racemate.

10th. Step ence of a lower alkanol, such as methanol, by treatment with an acid, for examplea hydrohalic acid, e.g. hydrochloric acid, into a compound of the formula VIII, wherein Z represents a lower alkoxy, e.g. methoxy, its racemate or an acid addition salt thereof. The reaction can be carried out at slightly reduced or elevated temperature, e.g. between about 0 and 50C. It is also possible here to resolve an optionally resulting racemate.

Steps 8-10, i.e., the epoxidation of an olefine, amininolysis of the epoxide and splitting of the 6-10 bond in the tricyclic skeleton, can also be carried out in another sequence. For example, in an a-epoxide of the formula VI, or its racemate, the 6-10 bond can be split according to the reaction conditions of the 10th. step, and in the resulting 2,3endoepoxy4-endo-hydroxy-8-alkoxy- 7-oxabicyclo[4,3,0]nonane of the formula VI, or in the racemate thereof, the epoxy grouping can be aminolysed according to the method of the 9th. step, in the process of which a compound of the formula VIII, or its racemate, is formed. Furthermore, in a tricyclic olefine of the formula V, or in its racemate, it is possible to cleave the 6-10 bond according to the reaction conditions of the 10th. step and, in the resulting bicyclic olefine of the formula V, or in its racemate, to epoxidise the double bond according to the method of the 8th. step, whereupon once again a compound of the formula VI, or its racemate, is obtained.

1 1th. Step From the compound of the formula VIII, its racemate or an acid addition salt thereof, it is possible to split off the amino group, in the process of which a ring contraction simultaneously takes place and an aldehyde of the formula IX, wherein Z, is lower alkoxy, such as methoxy, and Z is hydroxy, or its racemate, is formed. The splitting off can be performed by diazotisation, e.g. with nitrous acid, prepared in situ from one of its salts, such as sodium nitrite, and an acid, such as acetic acid,

or with an anhydride of nitrous acid, such as dinitrogen I tetroxide, in a solvent, such as water, or in an ethereal solvent, such as ethylene glycol monomethyl ether, preferably at reduced temperature, e.g. between about l0 and +50C. If desired, it is also possible to resolve an optionally obtained racemate by one of the methods described later herein, into both its optical antipodes.

1201. Step The aldehyde of the formula IX, wherein Z, represents methoxy and 2 represents hydroxy, or its racemate, can be used for the synthesis of primary steps which lead either to prostaglandin F ,1 or also to F The compound of the formula Xa can be manufactured therefrom by reaction with the Wittig reagent which is prepared in the conventional manner from 2-(S)- hydroxy-nheptyltriphenylphosphonium iodide and methyl lithium [E. J. Corey et al., Ann. New York Acad. Sci. 33 (1971)]. The reaction takes place at temperatures between about-78C and about 25C in tetrahydrofuran or ethylene glycol dimethyl ether, in the process of which a transdouble bond is formed. The compound of the formula Xb can be manufactured. therefrom in analogous manner by using the known Wittig reagent from cis-2-(S)-hydroxy-4-n-heptenyltriphenylphosphonium iodide [E. J. Corey et al., J. AM. Chem. Soc. 93, 1490 (1971)].

If the racemate consisting of the compound of the formula VI and its optical antipodes is used as starting material, there is obtained an diastereoisomer mixture which, with the aid of physicochemical separating operations, can be separated or further processed as such.

If instead of 2-(S)-hydroxy-n-heptyl-triphenylphosphonium iodide there is used racemic 2-hydroxy-nheptyl-triphenylphosphonium iodide or the corresponding heptenyl derivatives, once again a diastereoisomer mixture is obtained which likewise can either be further processed or separated by the aid of physicochemical separating operations. The same diastereoisomer mixture is obtained by using instead of the 2- hydroxy-heptyl-or 2-hydroxy-heptenylphosphonium compounds a corresponding 2-oxo-heptylor 2-oxoheptenyl derivative, e.g. l-triphenylphosphonium-2- heptanone-bromide or the l-triphenylphosphoranylidene-Z-heptanone prepared therefrom with sodium hydrogen carbonate [M. Miyano and C. R. Dorn, Tetrahedron Letters 1615 (1969)], and reducing the resulting ketones of the formula Xc with a complex hydride, such as sodium borohydride. The two racemates obtained thereby can again either be further processed as such or resolved into their respective two optical antipodes with optically active auxiliary products by methods later described herein.

13th. Step The cyclic acetals of the formulae Xa and Xb, wherein Z represents e.g. methoxy and Z represents hydroxy, their racemates or the corresponding diastereoisomer mixtures, are hydrolysed under acid conditions to the compound of the formula XIa or Xlb or to their racemates.

These compounds can be in the form of the free aldehyde or in that of the cyclic hemiacetal of the formula XII. In using optically active starting material of the formula Xa or Xb, the trihydroxy compounds already contain all steric prerequisites for their conversion in the next step into the natural, optically active PGF: and PGF If a start is made from the racemate of a compound of the formula Xa or Xb, the racemate is obtained which consists of a mixture of the compound of the formula XIa or Xlb and the optical antipodes thereof. The separation of the racemate can be effected by one of the conventional processes later described herein. By starting from the diastereoisomer mixtures which may be obtained in the 12th. step, once again diasteroisomer mixtures are obtained which can be further processed as such or resolved analogous to the methods mentioned in the 12th. step.

14th. Step The compounds of the formula XIa or Xlb, corresponding hemiacetals of the formula Xlla or XIIb or also the corresponding racemates or diastereoisomer mixtures, are finally converted with the Wittig reagent from -triphenylphosphonovaleric acid [E. J. Corey, T. K. Schaaf, W. Huber, U. Koelliker and N. M. Weinshenker, J. Amer. Chem. Soc. 92, 397 (1970) and 91, 5675 (1969)] in dimethyl sulphoxide [R. Greenwald, M. Ch'aykowsky and E. J. Corey, J. Org. Chemi. 28, 1128 (1963)] into the prostaglandin P of the formula Xllla or P of the formula Xlllb, Preferably a cis-double bond is formed in this reaction.

The natural, optically active PGF or F is obtained directly by using optically active starting material of the formulae XIa or Xlb, Xlla or Xllb. By starting from the racemate of the compound of the formula XIa or Xlb or Xlla or Xllb, a racemate is obtained which consists of a mixture of natural PGF and PGF and the optical antipodes thereof. The racemate separation can be effected by one of the conventional methods later described herein.

If a start is made from the diastereoisomer mixtures which may be obtained in the 13th. step, once again mixtures are obtained which consist of the naturally occurring prostaglandin F and F and their diastereoisomers, which can be used as such or resolved as mentioned in the 12th. step. 7

The racemates mentioned hereinbefore an be resolved into their optical antipodes by methods which are known per se.

One of these methods consists in reacting a racemate with an optically active auxiliary substance, separating the resulting mixture of two diastereoisomer compounds with the aid of appropriate physicochemical. methods and then resolving the individual diastereoisomeric compounds into the optically active starting materials.

Particularly suitable racemates for resolution into the antipodes are those which posses an acid group, e.g. the racemate of the compound of the formula XIII. Itis possible to convert other described racemates into acid racemates by simple reactions. For example, the aidehydes of the formulae IX and XI react with a hydrazine derivative carrying an acid group, e.g. 4-(4-carboxyphenyl)-semicarbazide, to give the corresponding hy-- drazone derivatives, or the alcohols of the formulae IV. VIII or X react with a dicarboxylic anhydrideeg.

phthalic anhydride, to give the racemate of an acid half ester.

These acid racemates can be reacted with optically.

active bases, e.g. esters of optically active aminoacids, or (-)-brucine, (+)-quinidine, ()quinine, (+)-quinquonine, (+)-dehydroabietylamine, and

ephedrine, (+)-and ()-l-phenyl-ethylamine or the N- monoor dialkylated derivatives thereof, to give mixtures consisting of two diastereoisomeric salts.

The racemates cited hereinbefore which contain hydroxy groups can also be resolved into their optical antipodes, for which purpose there are used in particular optically active acids, or reactive functional derivatives thereof, which form diastereoisomeric esters with the cited alcohols. Examples of such acids are: ()-abietic acid, D(+)-and L()-malic acid, N-acylated optically active aminoacids, and ()-camphanic acid,

It is possible for basic racemates, such as those of the formulae VII and VIII, to form diastereoisomeric salts with the above cited acids.

Racemates which contain double bonds can be converted, for example with platinum chloride and (+)-l-phenyl-Z-aminopropane, into mixtures of diastereoisomeric complex salts.

Physicochemical methods are suitable for separating the distereoisomeric mixtures, chiefly fractionated crystallisation. But chromatographic methods canalso be used, primarily solid-liquid chromatography. Readily volatile diastereoisomeric mixtures can be separated also by distillation or gas chromatography.

The resolution of the separated diastereoisomeric compounds into the optically active starting materials is also performed by conventional methods.

The acids or bases are liberated from the salts, e.g. by treatment with acids or bases which are stronger than those originally used. From the esters and urethanes are obtained the desired optically active compounds, for example by alkaline hydrolysis or by reduction with a complex hydride, such as lithium aluminium hydride.

A further method of resolving the racemates consists in chromatography on optically active absorption layers, for example on cane sugar.

According to a third method, the racemates are dissolved in an optically active solvent and the more sparingly soluble optical antipode is crystallised out.

In a fourth method, the varying reactivity of the optical antipodes to biological material, such as microorganisms or isolated enzymes, is utilised.

In a fifth method, the racemates are dissolved and one of the optical antipodes is crystallised by inoculation with a small amount of an optically active product obtained by the above methods.

The term lower used to qualify the syllable alk, e.g. in lower alkane, lower alkyl, lower alkoxy, lower alkylene and the like, indicates that the respective hydrocarbon radicals contain up to 7 carbon atoms, but in general up to 4 carbon atoms are preferred.

In the compounds of the present invention it is possible for a hydroxy group to be etherified e.g. by a substituted lower alkanol, for example a lower alkanol containing halogen or phenyl, such as 2-iodoethanol, trichloro-ethanol, benzyl alcohol, diphenyl methanol, triphenyl carbinol, 2-phenethyl alcohol, or preferably by a lower alkanol or a cycloalkanol with 5 to 7 carbon atoms, in which one of the methylene groups, in particular that in the position, can be replaced by a heteroatom, preferably by oxygen. Examples of these latter are methanol, ethanol, cyclopentanol, cyclohexanol tetrahydroxypyran-2-ol and a 1-lower alkoxy-lower alkanol such as l-ethoxy ethanol.

A hydroxy group can also be etherified with a trilower alkylsilyl, such as a trimethylsilyl or or dimethyl tert. butylsilyl group.

In the compounds according to the invention, a hydroxy group can be esterified for example with a weak acid, such as an aliphatic monocarboxylic acid, preferably with a lower alkanecarboxylic acid e.g. acetic acid, also with a lower alkanecarboxylic acid substituted e.g. by halogen, such as trifluoroor trichloroacetic acid, with an aliphatic dicarboxylic acid, such as oxalic or malonic acid, with an aromatic carboxylic acid e.g. with a benzoic acid, which can be optionally substituted by alkyl, phenyl, nitro or halogen, such as benzoic acid, p-methyl-benzoic acid, p-biphenylcarboxylic acid, nitrobenzoic acid or p-chloro-benzoic acid, or also with an aromatic dicarboxylic acid, e.g. with an optionally substituted benzene dicarboxylic acid, such as phthalic acid.

In preferred compounds of the formula VIII and their racemates Z is an etherified hydroxy group, in particular a hydroxy group, etherified with a lower alkanol.

Acid addition salts of compounds of the formula VIII, their optical antipodes and racemates, are those with inorganic and organic acids, for example with hydrohalic acids, such as hydrochloric acid, with oxyacids, such as sulphuric acid, with lower alkanesulphonic or benzenesulphonic acids which are optionally substituted by e.g. halogen, lower alkyl or phenyl such as methaneor toluenesulphonic acid, or the corresponding carboxylic acids, such as acetic acid or pmethylbenzoic acid, as well as with the optically active acids cited hereibefore.

A compound of the formula VIII, the optical antipode and racemate thereof, can be manufactured by solvolysing a compound of the formula VIII or the optical antipode or racemate thereof or an acid addition salt thereof, with a compound of the formula 2 H, in which Z has the meaning given under the formula VIII, and, if desired, converting a resulting compound within the compass of the final products and/or, if desired, resolving an optionally resulting racemate into the optical'antipodes.

For the solvolysis it is possible to use as compound of the formula Z I-l water, one of the alchohols cited hereinabove, preferably a lower alkanol, such as methanol, or one of the acids cited hereinabove, preferably a lower alkanecarboxylic acid, such as acetic acid. The

.process is preferably carried out in the presence of an acid catalyst, such as a Lewis acid, e.g. of a halide, such as fluorine, chloride or bromide, of boron, aluminium, titanium, tin, phosphorus, antimony or iron, preferably of boron trifluoride, or of a proton acid, e.g. a hydrohalic acid, such as hydrochloric acid, an oxyacid, such as sulphuric acid, a sulphonic acid, such as a lower alkaneor benzenesulphonic acid which is optionally substituted by e.g. halogen, alkyl or phenyl, such as methane or toluenesulphonic acid, also of an acid ion exchanger. As solvent there is used preferably an excess of the agent required for the solvolysis in the presence or absence of a diluent, such as an ethereal solvent, e.g. a di-lower alkyl ether or cyclic ether, such as dioxan. The reaction temperature can be reduced or slightly elevated, for example between about 0 and 50C.

The compound of the formula VIII, the optical antipode and racemate thereof and acid addition salts thereof, can be manufactured by a further process variant by reacting an endoepoxide of the formula VI Ol-I if desired, converting a resulting compound within the compass of the final products and/or, if desired, resolving an optionally resulting racemate into the optical antipodes.

Preferably ammonia is used, also as its reactive functional derivative a salt thereof, e.g. with a weak acid, such as carbonic acid, or a metal amide, for example an alkali amide, such as a sodium amide. The process can be carried out in the presence or absence of a solvent. As solvent it is possible to use water or organic solvents, for example lower alkanols, such as ethanol, ethereal solvents, such as ethylene glycol di-lower alkyl ethers, e.g. ethylene glycol dimethyl ether, or lower alaknecarboxylic acid amides which are optionally substituted by lower alkyl, such as formamide or dimethyl formamide. The reaction is carried out preferably at elevated temperature, for example between about 50 and 150C, optionally under pressure.

In this reaction there is formed the 4-exo-amino-5- endo-hydroxy compound of the formula VIII, and its optical antipode or racemate. The isomeric compound with 5exoamino-4-endo-hydroxy structure and its optical antipode or racemate are either not obtained or are obtained in undectably small amounts.

Within the defined scope it is possible to convert a free, etherified or esterified hydroxy group Z into another group falling under this definition. For example, it is possible to esterify or etherify a compound of the formula VIII, wherein Z, is a free hydroxy group, and its optical antipode or racemate, by treatment with an alcohol or acid falling under the formula Z I-I in the presence of one of the acid catalyst cited hereinabove. Furthermore, in a compound of the formula VIII, or its optical antipode or racemate, wherein Z is an etherified or esterified hydroxy group, it is possible to hydrolyse, transetherify or transesterify this latter by treatment with water, or with another alcohol or acid falling under the formula Z H in the presence of one of the acid catalyst cited hereinabove.

A resultng amine can be converted into an acid addition salt e.g. by reaction with an inorganic or organic acid or a corresponding anion exchanger and isolation of the salt which has formed. A resulting acid addition salt can be converted into the free compound e.g. by treatment with a base, such as an alkali metal hydroxide, ammonia or a hydroxy] ion exchanger.

The salts can also be used for the purification and identification of the free compounds; thus free compounds can be converted into their salts, these isolated from the crude mixture and the free compounds then obtained from the isolated salts. Because of the close relationship of the new compounds in the free form and in the form their salts, what has been said above and is stated hereinafter with reference to the free compounds or the salts refers also to the corresponding salts and free compounds, wherever this applies.

The invention also comprises those embodiments of the process in which a start is made from compounds which are obtainable as intermediate products at any stage and the missing steps of the process are carried out with these, or the process is discontinued at any stage; it is also possible to use starting materials in the form of derivatives or which are formed during the reaction.

Preferred starting materials and reaction conditions are those which lead to the compounds cited at the outset as being especially preferred.

which is also used as starting material, and its optical antipode and racemate, can be manufactured by the process variant following on the 10th. step.

The following Examples illustrate the invention, but without being in any way limitative thereof.

EXAMPLE 1 A mixture of 1.056 g (8 mmols) of cis-cyclohexane- 1,3,5-triol, 1.072 g (11.6 mmols) of glyoxylic monohydrate, 2.0 g (10.5 mmols) of p-toluenesulphonic monohydrate, 50 ml of benzene and 10 ml of water is boiled under reflux for 16 hours in a Dean-Stark steam trap. After the reaction solution has cooled, it is decanted off from a small amount of undissolved resin, washed with 20 ml of a solution which is saturated with sodium chloride and sodium bicarbonate, and with 35 ml of water. The combined washings are extracted with methylene chloride and the methylene chloride layer is combined with the benzene solution, dried over sodium sulphate and concentrated in a water jet vacuum. The residue is recrystallised from methylene chloride/ether to give 2,- 5,1l-trioxatricyclo[4,3,l ,1 undecan-3-one of the formula Ia which melts at l40l43C.

EXAMPLE 1a While stirring, 10.56 g (0.08 mols) of cis-cyclohex ane-1,3,5-triol and 10.72 g (0.116 mols) of glyoxylic monohydrate in 400 ml of ethylene glycol dimethyl ether are heated until all is dissolved. To the cooled solution are added carefully 96 g of Amberlyst l5 (strongly acid catalyst in pearl form, Rohm and Haas Co.) [dried for 4 hours at 110C and 0.05 Torr]. The resulting suspension is boiled underrefiux for 30 minutes, cooled and filtered. The Amberlyst which is filtered off is washed twice with 60 ml of ethylene glycol dimethyl ether each time and then with 1,000 ml of methylene chloride. The filtrate is combined with the washings and extracted with 400 ml of normal sodium bicarbonate solution. The sodium bicarbonate solution is washed with 300 ml of methylene chloride, the methylene chloride solution is combined with the previously obtained organic solutions and these are dried over sodium sulphate and evaporatedin a water jet vacuum. The crystalline residue is recrystallised from methylene chloride/ether to give 2,5,1 l-trioxatricyclo[4,3,l,l ]undecan-3-one of the formulala (m.p. l40l43C).

EXAMPLE lb A mixture of 500 mg (0.378 mmols) of cis-cyclohexane-l,3,5 -triol and 920 mg (0.567 mmols) of methyl diethoxyacet'ate in ml of ethylene glycol dimethyl ether is heated under reflux, treated after 15 minutes with 2 g of predried Amberlyst 15 (see Example la) and boiled for a further 10 hours under reflux with stirring. The catalyst is filtered off hot and washed twice with 20 ml of methylene chloride. The filtrate is concentrated under reduced pressure, the residue is taken up in the combined methylene chloride fractions and the resulting solution is shaken with 10 ml of water. The isolated aqueous layer is extracted with 10 ml of methylene chloride and the combined methylene chloride fractions are dried with anhydrous sodium sulphate and the solvent is distilled off. The crystalline residue is treated with 2 ml of ether and the crystalline 2,- 5,1l-trioxatricyclo[4,3,l,1"- }undecan-3-one of the formula la is collected by suction filtration (m.p. l40l43C).

EXAMPLE 2 a. Analogous to Example 1, the 2,5,1 l-trioxatricyclo [4,3,l,l ],undecan-3-ol of the formula lb is obtained from the glyoxal hydrate and cis-cyclohexane-'1,3,5-triol. Melting point: l85194C.

b. To a stirred solution of 340 mg of 3,5,11- trioxatricyclo[4,3,l,l- ]undecan-3-one are added dropwise within 10 minutes under nitrogen and at room temperature, 2.8 ml of a 20 percent solution of.

. c. A solution of 340 mg of 2,5,1 l-trioxatricyclo[4,3,l ,l ]undecan-3-one in 10 ml of absolute ethanol is treated with 300 mg of sodium. After the metal has dissolved the reaction mixture is treated with 10 ml of water and 0.7 ml of acetic acid, concentrated under reduced pressure to about 3 ml and the concentrate is extracted with methylene chloride. The solvent is evaporated to leave as residue pure 2,5,1 l-trioxatricyclo- [4,3,1,l ]undecan-3-ol.

EXAMPLE 3 A solution of 8.50 g (0.05 mols) of 2,5,11- trioxatricyclo[4,3,1,1 ]undecan-3-one of the formula la in ml of ethylene glycol dimethyl ether is added dropwise within 15 minutes, while stirring and cooling with ice, to a suspension of 2.0g (0.05 mols) of lithium aluminium hydride in 60 ml of ethylene glycol dimethyl ether. The reaction mixture is boiled for 15 minutes under reflux, cooled to room temperature and carefully treated with 10 ml of ethyl acetate to destroy excess lithium aluminium hydride. Then, while stirring, 2.0 ml of water, 2.0 m1 of 15 percent sodium hydroxide solution, and finally 6 ml of water, are added to the reaction mixture. The precipitated salts are filtered off, stirred with ml of methylene chloride and filtered again. The combined filtrates are concentrated in a water jet vacuum. The crystalline residue is recrystallised from methylene chloride to give 3-hydroxymethyl-2,4- dioxabicyclo[3,3,l ]nonan-7-ol of the formula lla m.p. l49151C.

(Ila) EXAMPLE 3a A solution of 340 mg of 2,5,1 l-trioxatricyclo[4,3,l,l' undecan-3-one of the formula la in 10 ml of absolute ethanol is treated at room temperature with mg of sodium borohydride and the mixture is stirred for 2 hours. The reaction mixture is diluted with 10 ml of water, the pH adjusted to 8 with a few drops of glacial acetic acid and the resulting solution is concentrated under reduced pressure to about 3 ml. The concentrate is extracted three times with altogether 100 ml of methylene chloride, the combined extracts are dried with sodium sulphate and the solvent is distilled off to give 3-hydroxymethyl-2,4- dioxabicyclo[3,3,l ]nonan-7-ol of the formula Ila, which melts at l46149C.

EXAMPLE 3b A similar 3 hour reduction of 340 mg of 2,5,11- trioxatricyclo[4,3,1,l"' ]undecan3-one of the formula la in 10 ml of isopropanol with 150 mg of sodium borohydride at 50C, and subsequent working up as described hereinabove, leads to the same compound of the formula lla.

EXAMPLE 30 To a solution of 340 mg (2mmols) of 2,5,11- trioxatricyclo[4,3,l,l' ]undecan-3-one in 10 ml of methanol are added all at once 150 mg of sodium borohydride while stirring and cooling to l2-15C (water bath). After 1 /2 hours, during which time the bath temperature is allowed to rise to 20C, a further 150 mg of sodium borohydride are added and the mixture is stirred for 2 /2 hours at 20C. The reaction mixture is then treated with 10 ml of water, the pH adjusted to 8 with a few drops of acetic acid, and concentrated under reduced pressure to about 3 ml. The concentrate is extracted three times with 25 ml of methylene chloride on each occasion, the combined extracts are dried over sodium sulphate and the solvent is distilled off (at the conclusion under reduced pressure) to give crystalline 3-hydroxymethyl-2,4-dioxabicyclo [3,3,1]nonan-7-ol of the formula lla (m.p. l46149C).

EXAMPLE 4 A solution of 0.87 g (5 mmols) of 3-hydroxymethyl- 2,4-dioxabicyclo[ 3,3,1 ]nonan-7-ol of the formula lla in 5 ml of anhydrous pyridine is cooled to -20C and, while stirring, treated with 1,1 ml (14,2 mmols) of methanesulphonyl chloride. The cooling bath is removed and the reaction mixture is added after 1 A hours to 40 ml of a normal sodium bicarbonate solution. The resulting mixture is extracted successively with 40 ml of ethyl acetate and 40 ml of methylene chloride. The combined organic solutions are washed with 10 ml of sodium bicarbonate solution, dried over magnesium sulphate and concentrated in a water jet vacuum. The crude product is recrystallised from acetone/heptane and gives 7-methylsulphonyloxy-3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3,3 ,1 ]no nane of the formula llb OSO 0H m.p. 137-13sc.

EXAMPLE 5 To a solution of 348 mg (2 mmols) of 3- hydroxymethyl-2,4-dioxabicyclo[3,3,l ]nonan-7-ol of the formula Ila in 2.0 ml of absolute pyridine are added at l5C with stirring 1.28 g of p-bromobenzenesulphochloride all at once and the resulting mixture is further stirred under nitrogen for 48 hours at room temperature. The reaction mixture is treated with 25 ml of methylene chloride and shaken succesively with 15 ml of 8 percent NaHCO and 15 ml of sodium chloride solution. The aqueous layers are extracted once more with methylene chloride. The combined organic phases are dried over sodium sulphate and freed from solvent and pyridine in a water jet vacuum and finally in an oil pump, to leave as residue crude 7-(pbromophenylsulphonyloxy)-3-( pbromophenylsulphonyloxymethyl)-2,4-dioxabicyclo [3,3,1 ]nonane of the formula 110 16 which congeals to a crystalline'solid on standing. It is crystallised from boiling benzene with the addition of I a small amount of hexane. Melting point: 128C; the crystals contain 2/3 mols of benzene.

EXAMPLE 6 A solution of 1.65 g (5 mmols) of 7- methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4-

dioxabicyclo[3,3,l ]nonane of the formula llb and 3.0

ml (20 mmols) of l,5-diazabicyclo[5,4,0]-undec-5'ene in 25 ml of anhydrous dimethyl sulphoxide is heated for 45 minutes to l 10C. The reaction mixture is cooled to room temperature and then diluted with 150 ml of ether. It is then washed successively with ml of Zn hydrochloric acid, 100 ml of water and finally with 100 ml of normal sodium bicarbonate solution. The aqueous layers are extracted separately twicewith 150 ml of ether on each occasion. The last ethereal extract is washed with 50 ml of water and each organic extract is finally washed with 50 ml of concentrated sodium chloride solution. The organic solutions are dried over magnesium sulphate and evaporated in a water jet vacuum.

Chromatography of the residue on basic aluminium oxide (activity level IV) with benzene as eluantre sults in a racemic mixture of 3-methylsulphonyloxymethyl- 2,4-dioxabicyclo[3,3,1] non-6-ene of the formula llla and its optical antipode, with a melting point of 54--59C.

EXAMPLE 6a A solution of 660 mg of 7-methylsulphonyloxy-3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3 ,3 ,1 ]nonane of the formula llb and 1.4 g of tetrabutylammonium fluoride in 7.5 ml of dimethyl formamide is heated under nitrogen for 7 hours to 60C. The cooled reaction mixture is treated with 20 ml of methylene chloride and ml of ether and shaken successively with 80 ml of an 8 percent bicarbonate solution, ml of water and 50 ml of sodium chloride solution. The aqueous layers are extracted separately twice with 100 ml. of the same solvent mixture on each occasion. The combined organic fractions are dried over sodium sulphate.'The solvent is distilled off under reduced pressure to give an oily product whose spectrum properties correspond to those of the pure racemic 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3,3,1 non-6-ene of the formula Illa. Preparative chromatog- EXAMPLE 6 b A mixture of 300 mg (0.91 mmols)" of .7--

methylsulphonyloxy. 3-methylsulphonyloxymethyl-2,4-

H i H Br- Q -SO 0- (:1-1 OO g 0.50 G Br (11c) dioxabicyclo[3,3,l]nonane of the formula Ilb and 15 ml of anhydrous toluene is heated to 80C and treated within 2 hours in amounts of altogether 300 mg of potassium tert.butylate dissolved in 5 ml of tert.butanol. The reaction mixture is stirred for a further 2 hours, then cooled, treated with saturated sodium chloride solution and extracted 5 times with ml of methylene chloride on each occasion. The combined organic extracts are washed once more with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Preparative chromatography of the resulting residue on silica gel with ethyl acetate as eluant yields a racemic mixture consisting of 3- methylsulphonyloxymethyl-Z,4-dioxabicyclo[ 3,3 ,1]- non-6-ene of the formula llla and its optical antipode of melting point 5058C.

EXAMPLE 6c A solution of 60 mg (0,18 mmoles) of 7- methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4- dioxabicyclo[3,3,l]nonane of the formula Ilb in 3 ml of ethylene glycol dimethyl ether (filtered through basic aluminium oxide) is heated to 80C and treated with a solution of 60 mg (0.54 mmols) of sublimed potassium tert. butylate in 0.7 ml of tert. butanol. The reaction mixture is cooled after 4 hours, treated with a saturated sodium chloride solution and extracted 5 times with 6 ml of methylene chloride on each occasion. The organic phases are dried over magnesium sulphate, and the solvent is evaporated. Preparative layer chromatography on silica gel with ethyl acetate as eluant yields a racemic mixture consisting of 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3,3,1 non-6-ene and its optical antipode.

EXAMPLE 6d A solution of 80 mg (0,24 mmoles) methylsulphonyloxy-3-methylsulphonyloxy-methyl- 2,4-dioxabicyclo[3,3,1]nonane of the formula Ilb in 2 ml in dimethyl sulphoxide (which has been dried over calcium hydride) is treated dropwise within 10 minutes with a solution of 100 mg of potassium tert. butylate (0.89 mmols) in 3 ml of dimethyl sulphoxide. The reaction temperature is kept at C. The reaction mixture is then diluted with 10 ml of ether and washed with 8 ml of 0.5 n hydrochloric acid and 10 ml of saturated sodium bicarbonate solution. The aqueous layers are extracted twice with 10 ml of ether on each occasion. The combined organic phases are washed again with 5 ml of sodium bicarbonate solution and 10 ml of water, dried over magnesium sulphate and concentrated in vacuo to give a racemic mixture consisting of 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3 ,3,1 non-6-ene of formula Illa and its optical antipode.

EXAMPLE 6e A solution of 100 mg (0.3 mmols) of 7- methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4- dioxabicyclo[3,3,1]nonane of the formula Ilb in Sml of tert. butanol (distilled over calcium hydride) is heated to 80C and 60 mg (0.54 mmols) of sublimed potassium tert.butylate dissolved in 2 ml of tert.butanol are added within 1 hour. The reaction mixture is heated for 6 hours at the same temperature, and then a further 11.0 mg (0.1 mmols) of potassium tert. butylate, dissolved in 0.5 ml of tert. butanol, are added. The reaction mixture is heated for a further hour, cooled,

treated with 40 ml of ether and washed 5 times with 15 'ml of water each time. The organic phase is dried over magnesium sulphate and evaporated to give a racemic mixture consisting of 3-methylsulphonyloxymethyl-Z,4- dioxabicyclo[3,3,1]non-6-ene of the formula llla and its optical antipodes, in the form of a colourless oil which crystallises on standing and is sufficiently pure for use in the following reaction.

EXAMPLE 6f 7-methylsulphonyloxy-3-methylsulphonyloxymethyl- 2,4-dioxabicyclo[3,3,l ]nonane (280 mg) is added to 5 ml of a boiling 2n potassium hydroxide solution in absolute alcohol and the mixture is boiled for 2 minutes under reflux while stirring vigorously. The reaction mixture which has congealed to a crystalline solid is cooled and, after treatment with 5 ml of 8 percent sodium bicarbonate solution, extracted three times with methylene chloride. The combined extracts are dried with sodium sulphate and the solvent is distilled off under reduced pressure to leave as residue the crystalline racemic 3-methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3,3,1 ]non-6-ene (m.p. 5356).

EXAMPLE 6g To a hot suspension of 280 mg of 7- methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4- dioxabicyclo[3,3,l ]nonane in 2,5 ml of isopropanol is added 2,5 ml of a boiling 2 n potassium hydroxide solution in isopropanol while stirring vigorously, and the resulting reaction mixture is boiled under reflux for 3 minutes. The reaction mixture is cooled and treated with 5 ml of an 8 percent sodium bicarbonate solution, then extracted 3 times with methylene chloride. The combined extracts are dried over sodium sulphate and the solvent is distilled off in vacuo under reduced pressure to leave as residue the racemic 3- methylslphonyloxymethyl-2,4-dioxabicyclo[ 3,3,1 ]non- 6-ene in the form of a colourless oil, which soon congeals to a crystalline solid (m.p. 5356C).

EXAMPLE 7 A solution of 61 bromophenylsulphonyloxy )-3-(pbromophenylsulphonyloxymethyl)-2,4-dioxabicyclo[3,3,1]nonane of the formula [[0 and 220 mg of tetra-n-butylammonium fluoride in 1.0 m1 of anhydrous dimethyl formamide is heated with stirring in a nitrogen atmosphere for 45 minutes to C. The cooled reaction mixture is treated with 5 ml of methylene chloride and 25 ml of ether and shaken succesively with 8 ml of normal sodium bicarbonate solution, 10 ml of water and 10 ml of sodium chloride solution. The aqueous phases are extracted twice with 10 ml of the same solvent mixture on each occasion. All organic phases are dried together over sodium sulphate. The solvent is distilled off under reduced pressure to yield a racemic mg of 7-(pmixture consisting of 3-( pbromophenylsulphonyloxymethyl-2,4-dioxabicyclo[ 3,3,1 ]non-6-ene of the formula lllb H Br- -S0 0C)-I "kO 0 I I 1b) and its optical antipode; m.p. 1141 17C.

EXAMPLE 8 A solution of 363 mg (1.55 mmols) of racemic 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3 ,3,1 non 6-ene and 215 mg (1.55 mmols) of potassium carbonate in 3.6 ml of acetone and 18 m1 of water is stirred in a nitrogen atmosphere for 18 hours under reflux.

The cooled reaction mixture is extracted 3 times with 30 ml of methylene chloride on each occasion.

The combined methylene chloride layers are concentrated, the residue is taken up in ethyl acetate and filtered through a column of 10 g of basic aluminium oxide (activity level IV). Elution is performed with ethyl acetate. Concentration of the first 60 ml of eluate in a water jet vacuum yields a racemic mixture of 9,10- dioxatricyclo[4,3,l,0 ]decan-4B-o1 of the formula [Va and its optical antipode, which melts after recrystallisation at 134-l42C (210232C, sealed capillary).

EXAMPLE 8a A solution of 75 mg (0.32 mmols) of racemic 3- methylsulphonyloxymethy1-2,4-dioxabicyc1o[3,3, l non-6-ene of the formula 111a and 44 mg (0.32 mmols) of potassium carbonate in 0.5 ml of ethylene glycol dimethyl ether and 2.5 ml of water, is stirred for 18 hours under reflux in an oil bath which is kept at 100C. The cooled reaction solution is diluted with water, saturated with NaCl and extracted times with 10 ml of methylene chloride on each occasion. The combined extracts are dried over magnesium sulphate and concentrated. The residue is resolved by means of preparative layer chromatography (on silica gel, eluant: methylene chloride/acetone 1:1). A racemic mixture of 9,10- dioxatricyclo[4,3,1,0 ]decan-4B-ol of the formula IVa and its optical antipode is obtained.

EXAMPLE 8b ml of isopropanol in one amount. In a few seconds .a 1

clear solution temporarily forms from which, however, potassium mesylate soon begins to precipitate. After stirring vigorously for 3 minutes at the boiling temperature of the solvent, the reaction mixture which in the meantime has congealed to a crystalline solid is treated with a solution of 25 g of potassium bicarbonate in 1,250 ml of water and about 250 ml are distilled off under reduced pressure from the resulting clear solution. The reaction mixture is then brought to the original volume by adding water and boiled under reflux for 16 hours in a nitrogen atmosphere. It is then cooled,

(IVa) saturated with sodium chloride and repeatedly extracted with methylene chloride. The combined extracts are dried over sodium sulphate and the solvent is distilled off under reduced pressure to give the crystalline racemic mixture of 9,10-dioxatricyclo[4,3,l,0 ]decan-4B-ol and its optical antipode. In similar manner it is also possible to use a 2n solution of potassium hydroxide in ethanol or in water/ethylene glycol monomethyl ether (2:1) for the splitting off of the methanesulphonic acid. The product can be further used without purification or purified as follows via its acetate:

A solution of 1.46 g of the racemic 9,10- dioxatricyclo [4,3,1,0 ]decan-4/3-ol in 25 ml of pyridine and 8 ml of acetic anhydride is allowed to stand for 14 hours at room temperature and then evaporated in a high vacuum. The residue is recrystallised from diethyl ether to give the pure racemic 4/3-acetoxy-9,10- dioxatricyclo[4,,3,1,0 ]decane which melts at 9798C.

A solution of 198 mg of the pure racemic 4B-acetoxy-9,l0-dioxatricyclo [4,3,1,0 ]decane in 8 ml of ethanol and 2 ml of 2n aqueous potassium hydroxide is boiled under reflux for 1 hours in a nitrogen atmosphere. The ethanol is then distilled off in vacuo and the residue is extracted 4 times with 20 ml of methylene chloride on each occasion. The methylene chloride solutions are evaporated and the pure 9,10-

-dioxatricyclo[4,3, l ,0 ]decan-4B-ol is obtained, which after recrystallisation from benzene/cyclohexane melts at 250256C (sealed capillary).

EXAMPLE 8c A solution of 1.56 g (10.0 mmols) of the pure racemic 9,10-dioxatricyclo[4,3,1,0 ]decan-4B-ol (purified via the acetate) in 15 ml of pyridine is treated, while stirring, with 2.50 g(12.5 mmols) of (S)- ketopinylchloride (prepared from S-ketopinic acid with thionyl chloride/pyridine. s-ketopinic acid is prepared from (+)-l0-camphorsulphonic acid monohydrate analogous to the process described in Organic Synthesis 45, 14,55 The reaction mixture is stirred for 18 hours at room temperature and added to a mixture of 25 ml of saturated sodium carbonate solution and 25 m1 of water. The mixture is extracted 3 times with 50 m1 of methylene chloride on each occasion. The methylene chloride solution is treated with benzene, then evaporated in vacuo, and the residue recrystallised 4 times from ethyl acetate to give the pure 8S-4B-(S- detopinyloxy)-9,10-dioxatricyclo[4,3 ,1 ,0 ]decane,

[a],,= 47 (c=l in chloroform) which melts at l83185 C. The mother liquor contains the crude 8R- I 4B-( S-ketopinyloxy )-9, 1 O-dioxatricyclo 4,3 ,1 ,0

decane which melts at 11ll 14C. A solution of 1.28 g (4.0 mmols) of the pure 8S-,4B-(S-ketopinyloxy)- 9,l0-dioxatricyclo[4,3,l,0 ']decane and 8.0 ml of Zn aqueous potassium hydroxide in 32 ml of ethanol is boiled under reflux for 15 hours in a nitrogen atmosphere. The solution is then cooled, the ethanol evaporated in vacuo, the residue treated with 5 ml of water and extracted 6 times with 50 ml of methylene chloride on each occasion. The combined methylene chloride layers are evaporated, and the residue is first sublimed at l 10C (0.02 Torr) and then recrystallised from benzene/cyclohexane. The pure 8S-9, l 0- dioxatricyclo[4,3,1,0 ]decan-4B-ol of the formula lVa melts at 251-256C, [a],,=147 (c 1 in chloroform).

EXAMPLE 8a A solution of l .56'g 10.0 mmols) of the racemic 9,1- -dioxatricyc'lo[4,3,'l ,0 ]decan-4B-o1 (purified via the acetate) in 30 ml of dry benzene is boiledfor 14 hours under reflux with 1 ml of triethylamine and 2.2. g (15 mmols) of (-)-1-phenyl-ethylisocyanate. After evaporation in vacuo and drying in a high vacuum at 50C the residue is crystallisedout from ethyl acetate/hexane and recrystallised 5 times from benzene. The resulting pure urethane melts at l44l45C and has the following optical rotation: [04],, 32 (c l in chloroform). This urethane (50 mg) is boiled under reflux with 1.0 ml of Zn potassium hydroxide solution in ethanol. The mixture is then treated with water ml) and concentrated to 5 ml. The solution is washed 3 times with ml of pentane on each occasion, then concentrated to l ml and the concentrate is extracted 5 times with 20 ml of methylene chloride on each occasion. The combined methylene chloride solutions are filtered through cotton wool and evaporated. The residue, 8S-9,l0- dioxatricyclo[4,3,l,0 ]decan-4B-ol, has the optical rotation [01] -147 c l in chloroform).

In analogous manner it is possible to obtain the 8R- 9,l0-dioxatricyclo[4,3, l ,0 ]-decan-4B-ol with the optical rotation [a],, =+l47 (c l in chloroform) from the pure racemic 9,lO-dioxatricyclo[4,3,1,0 ]decan- 4/3ol with the aid of (+)-l-phenyl-ethylisocyanate.

EXAMPLE 8e to yield the pure racemic 9,10-dioxatricyclo [4,3,l,0 ]decan-4Bol.

EXAMPLE 9' While stirring, a solution of 024 ml of methanesulphonyl chloride in 5.0 ml of methylene chloride is added at a temperature of -l0C to a solution of 156 mg (Loo mmols) of racemic 9,10-dioxatricyclo[4,3,l ,0 ]decan-4B-o1 and 0.55ml.(4.00 mmols) of triethylamine in 5,0 ml of methylene chloride. After 40 minutes, during which time the cooling bath has warmed to 0C, the reaction mixture is diluted with ml of methylene chloride and washed'with 10ml of normal sodium bicarbonate solution.The sodium bicarbonate layer is washed with 10ml of methylene chloride and this methylene chloride layer is combined with the previous methylene chloride solution, dried over sodiumsulphate and concentrated in a'water jet vacuum. The residue is taken up in a small amount of ethyl acetate and filtered through a column of 5 g of basic aluminium oxide (activity level IV). After elution with ethyl acetate and concentrating the first 50 ml of the eluate there is obtained as residue 21 cruderacemic mixture of 4B-methylsulphonyloxy-9,lO-dioxatricyclo [4,3,1,0 ]decan of the formula lVb I (IVb) EXAMPLE 9a A solution of 550, mg (3.52 mmols) of the racemic 9,l0-dioxatricyclo[4,3,l,0 ]decan-4B-ol in 25 ml of ether (filtered over basic aluminium oxide) is treated with 900 mg of sodium hydride (50 percent) and the mixture is boiled under reflux for 3 hours. Then 2 ml of carbon disulphideare added and heating is continued for 3 hours. Finally, 2 ml of methyl iodide are added and the mixture is refluxed from a further 4 hours. The reaction mixture is cooled and excess sodium hydride is then destroyed with moist ether and subsequently with water. The organic phase is isolated and dried over magnesium sulphate. The solvent is expelled and the resulting oil is dissolved in benzene and filtered over aluminium oxide (activity level IV). After an, extremely unpleasant smelling component has passed out of the column the eluate is combined and evaporated. Repeated crystallization of the residue from heptane yields the racemic mixture consisting of 9, l 0-dioxatricyclo[4,3 l ,0 ]-decane-4B-methylxanthogenate of the formula IVc and its optical antipode; m.p. 8182C.

EXAMPLE 10 A solution of the crude racemic 4B- methylsulphonyloxy9,l0-dioxatricyclo[4,3,1 ,0 ]dec ane of the formula IVb, obtained in Example 9, in 1.0 ml of anhydrous dimethyl sulphoxide, is treated in a nitrogen atmosphere and with stirring with 2,5ml of a freshly prepared normal solution of potassium tert.butylate in anhydrous dimethyl sulphoxide, and the mixture is stirred for 40 minutes. The reaction solution is then diluted with 50 ml of ether and washed 4 times with 10 ml of water on each occasion and once with 20 ml of saturated sodium chloride solution. The organic layer is concentrated, the residue taken up in a small amount of methylene chloride and the solution is filtered through a column of 2 g of basic aluminium oxide (activity level IV). After elution with methylene chloride and concentrating the first 50 ml of eluate in a water jet vacuum there is obtained as residue the racemic mixture of 9,l-dioxatricyclo[4,3,l,0 ]dec-4-ene of the formula V and its optical antipode, in the form of a wax-like substance; m.p. lO3l05C. From 8S-4B- methylsulphonyloxy-9, l 0dioxatricyclo[4,3,l ,0 ]decane there is obtained in analogous manner 8S-9,l0-

dioxatricyclo[4,3,l,O ]dec-4-ene, m.p. lO8l 14C; [a],; +1 1 (c =1 in chloroform).

EXAMPLE lOa To a boiling solution of 4.68 g of racemic 4B- methylsulphonyloxy-9, 1 0-dioxatricyclo[4,3 l ,0 ]decane in 40 ml of isopropanol is added a hot solution of 4.48 g of potassium hydroxide in the same solvent in a single amount and the resulting reaction mixture is refluxed for 2 hours with stirring. During this time the reaction mixture congeals to a crystalline solid from the precipitated potassium mesylate. It is then treated with 100ml of 8 percent sodium bicarbonate solution and repeatedly extracted with methylene chloride. The combined extracts are dried over sodium sulphate and evaporated under reduced pressure. The resulting crude product is dissolved in pentane/ether (9:1) and filtered through a column filled with 100 go of aluminium oxide (activity level IV). The first 500 ml of eluate yield after evaporation the racemic mixture of 9,10- dioxatricyclo[4,3,l,0 ]dec-4-ene of the formula V, and its optical antipode.

EXAMPLE 10b To a solution of racemic 9 l0- dioxatricyclo 4,3 ,1 ,0 decane-4B-methylxanthogenate in methylene chloride is added the ten fold amount of sodium carbonate and the solvent is distilled off in a rotary evaporator. The resulting composition is heated to 150C in a pyrolysis tube. The distillate which is collected contains the racemic 9,10-dioxatricyclo [4,3 ,1 ,O ]dec-4-ene.

EXAMPLE 1 1 To a solution of 165 mg of racemic 9,10- dioxatricyclo [4,3,l,0 ]dec-4-ene in 4 ml of methanol are added, with stirring and at room temperature 865 mg of potassium bicarbonate and 740 mg of benzonitrile. To this mixture are added at intervals of 8 hours 5 portions each of 0.3 ml of 30 percent hydrogen peroxide and stirring is continued for 10 hours. Methylene chloride (25 ml) is then added to the reaction mixture, which is washed with 2 percent sodium hydrogen carbonate solution, dried over sodium sulphate and concentrated. Benzamide which has formed is removed by crystallisation from methylene chloride/pentane. The residual oil can be used directly in the next reaction, or

chromatographed on 22 g of basic aluminium oxide (activity level IV). Elution with petroleum ether/ben-v zene (7:3) yields the racemic mixture of 4B,5B-epoxy- 9,10-di0xatricyclo[4,3,l.O fidecane of the formula and its antipode, (m.p. after crystallisation from ether/- pentane: l8l182C), and also as main product the racemic mixture of 4oz,5a-epoxy-9,l0-dioxatricyclo[4,3,l ,O ]decane of the formula and its antipode; (m.p. after crystallisation from ether/- pentane: 146l56C).

From 8S-9, 10-dioxatricyclo[4,3, 1 ,0 ldec-4-ene there is obtained in analogous manner the 8S-4a,5aepoxy-9, l O-dioxatricyclo[4,3 1 ,0 decane Melting point: l69-l71 [01],, (c-'- l in chloroform) and the 8S-4a,5a-epoxy-9,l0-dioxatricyclo[4,3,l ,0 decane Melting point: 180-1 82, [a] --87 (c= 1 in chloroform) EXAMPLE 1 l a To a solution of 350 mg (2,53 mmols) of racemic 9,- 10-dioxatricyclo[4,3,l,O ]dec-4-ene in 45 ml of chloroform (filtered through aluminium oxide of activity level I) are added 1.1 g l l mmols) of finely powdered EXAMPLE 12 A solution of 800 mg (5.2 mmols) of racemic 401,501- epoxy-9,lO-dioxatricyclo[4,3,l,O ]decane in 35 ml of 24 percent aqueous ammonia is heated in a Carious tube under nitrogen for 1 hour at C (bath temperature). Upon cooling, the contents of the tube are evaporated to dryness. The crystalline residue is taken up in methylene chloride. The solvent is evaporated to give the pure racemic mixture of 4a-amino9,lO-dioxatricyclo[4,3,l,0 ]decan-5oz-ol of the formula and its optical antipode, in the form of colourless crystals (m.p. l78l80C; sublimation at about 140C).

In analogous manner there is obtained from the 8S- 4a,5a-epoxy-9, l O-dioxatricyclo[4,3,l ,O ]decane the 8S-4aamino-9,lO-dioxatricyclo[4,3,1,O ]decan-5aol; m.p. 176-178", [04],, l55 (c l chloroform).

EXAMPLE 12a A solution of 143 mg of the crude mixture of racemic 4a,5a-epoxy-9,lO-dioxatricyclo[4,3,1,O ]decane and the corresponding a-epoxide in 5 ml of 24 percent aqueous ammonia is heated in a Carious tube under nitrogen for 1 hour to 100C (bath temperature). Upon cooling, the contents of the tube are evaporated to dryness in vacuo, the residue is dissolved in 5 ml of water, and this solution is washed twice with 10ml of diethyl ether on each occasion to remove unreacted B-epoxide. The aqueous phase is concentrated to yield the pure racemic 4a-amino-9,10-dioxatricyclo[4,3,l,O decanSa-ol (m.p. 178180C).

EXAMPLE 13 oxabicyclo[4,3,0]nonane hydrochloricde racemate, consisting of the compound of the formula 2 HCl (VIII a) no" "on and its optical antipode, melts at 242-244C.

A solution of 35 mg of this hydrochloride in 5 ml of water is charged on to anion exchanger column (Dowex-1-OH) and eluted with 250 m1 of water. The aqueous solution is concentrated to leave as residue the free racemic 2-exo-amino-3,4-endo-dihydroxy-8- methoxy-7-oxabicyclo[4,3,0]nonane which melts at 96C.

From the 8S-4B-amino-9, IO-dioxatricyclo[4,3,l,0 ]decan-5oz-ol there is obtained in analogous manner the 6S-2-exo-amino-3,4-endo-dihydroxy- 8-methoxy-7-oxabicyclo[4,3,0]nonane hydrochloride; m.p. 235-6 [0th, -1 17 (c l chloroform).

EXAMPLE 14 A solution of 45.6 mg of racemic 9,10-dioxatricyc1o [4,3,1,0 ]dec-4-ene and 10 mg of p-toluenesulphonic acid in 1.0 ml of methanol is stirred for 45 minutes at room temperature, treated with 3 ml of sodium bicarbonate solution (8 percent) and extracted 3 times with ethyl acetate. The combined extracts are dried over sodium sulphate and evaporated in vacuo. The oily residue is the racemic 4-endo-hydroxy-8-methoxy-7- oxabicyclo[4,3,0]non-2-ene(thin layer chromatography on silica gel with ethyl acetate as eluant, RF: 0.36) consisting of the compound of the formula OCH 3 and its optical antipode.

EXAMPLE 15 A solution of 51 mg of the racemic 4-endo-hydroxy- 8-methoxy-7-oxabicyclo[4,3,0]non-2-ene in 3ml of methylene chloride is stirred at room temperature for 26% hours in the presence of an excess of potassium bicarbonate. Then 5 ml of methylene chloride are added, the mixture is extracted with 3 ml of 2 percent sodium bicarbonate solution, and the methylene chloride phase is dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on 7 g of aluminium oxide (activity level IV), in the course of which the racemic mixture consisting of 2,3-exoepoxy-4-endo-hydroxy-8-methoxy-7- oxabicyclo[4,3,0]nonane of the formula and its optical antipode is eluted with methylene chloride. Elution with ethyl acetate/methanol (9:1) yields the racemic mixture consisting of 2,3-endo-epoxy-4- endo-hydroxy-8-methoxy-7-oxabicyclo[4,3,0]nonane of the formula A mixture of 51 mg of the racemic 4-endo-hydroxy- 8methoxy-7-oxabicyclo[4,3,0]non-2ene, lml of methanol, 183 mg of benzonitrile, 217 mg of potassium bicarbonate and 34mg of 90% hydrogen peroxide is stirred at room temperature and treated after 17 and 26 hours respectively with 34 mg of 90% hydrogen peroxide on each occasion. After a further 16 hours 3 ml of water and 10 ml of methylene chloride are added. The organic phase is isolated, extracted 3 times with 10 percent sodium bicarbonate solution, the aqueous extracts are reextracted 3 times with methylene chloride and the combined organic phases are dried over sodium sulphate and evaporated. The benzamide is removed from the resulting reaction product by crystallisation from methylene chloride/pentane and the residue is chromatographed on 7 g of aluminium oxide (activity level IV). Elution with methylene chloride/ethyl acetate (5:1) yields the racemic mixture consisting of 2,3-exoepoxy-4-endo-hydroxy-8-methoxy-7-oxabicyclo [4,3,0]nonane and its optical antipode. Further elution with ethyl acetate/methanol (9:1) yields the racemic mixture consisting of 2,3-endo-epoxy-4-endo-hydroxy- 8-methoxy-7-oxabicyclo[4,3,0]nonane and its optical antipode.

EXAMPLE 15b A solution of 64 mg of the racemic 4-endo-acetoxy- 4O 8-methoxy-7-oxabicyclo[4,3,0]non-2-ene, 207 mg of N-bromacetamide in ml of acetone and 6 ml of water is stirred for 16 hours at room temperature and the acetone is subsequently removed in vacuo. The aqueous solution is extracted with altogether 19 ml of methylene chloride and the methylene chloride extracts are washed with 2 ml of 2 percent sodium thiosulphate solution, dried over sodium sulphate and evaporated. Preparative thin layer chormatography of the residue on silica gel (methylene chloride/ethyl acetate 4:1) yields a mixture of isomeric bromohydrins. This mixture is stirred for 1 hour in 2 ml of 2.5 percent potassium hydroxide in methanol and to the mixture are added 20 ml of water and sodium chloride until saturation is reached. The saturated solution is then extracted 4 times with 15 ml of methylene chloride on: each occasion. The methylene chloride solution is dried over sodium sulpahte and then evaporated. The residue is resolved analogous to Example 15a into the racemic 2,3-endo-epoxy-4-endo-hydroxy-S-methoxy- 7-oxabicyclo [4,3,0]nonane and the corresponding 2,3-exo-epoxy racemate.

The starting material is obtained in the following manner:

A solution of 170 mg of the racemic 4-endo-hydroxy- 8-methoxy-7-oxabicyclo[4,3,0]non-2-ene in 1.5 ml of acetic anhydride and 5 m1 of pyridine is stirred for 5 hours at room temperature. Volatile components are distilled off in a high vacuum, again at room temperature, and the residue is treated with toluene and distillation performed once more. The oily residue is chromatographed on preparative silica gel plates with ethyl acetate. The racemic 4-endo-acetoxy-8-methoxy-7- oxabicyclo[4,3,0]non-2-ene is obtained as an oily product.

EXAMPLE 150 A solution of 62mg racemic 4a,5a-epoxy-9,l0- dioxatricyclo [4,3,1,0 ]decane in 6 ml of dry methanol is treated at 0C with 6 mg of p-toluenesulphonic acid and stirred at the same temperature for 1 hour. Then 50mg of fine by pulverised potassium bicarbonate are added and the mixture is stirred for 5 minutes. filtered and evaporated. The residue consists of a racemic mixture of 2,3-endo-epoxy-4-endo-hydroxy-8- methoxy-loxabicyclo [4,3,0]nonane of the formula VI'a and its optical antipode.

EXAMPLE 16 A solution of 30 mg of the racemic 2,3-endo-epoxy- 4-endo-hydroxy-8-methoxy-7- oxabicyclo[4,3,0]nonane in 0.3 ml of dioxaan and 2 ml of 24 percent aqueous ammonia is heated in a sealed test tube for 1 hour to 120C. The product is evaporated in vacuo, whereupon the racemic mixture consisting of 2-exo-amino-3,4-endo-dihydroxy-8-methoxy- 7-oxabicyclo [4,3,0]nonane of the formula VIII, and its optical antipode, is obtained as a colourless oil.

EXAMPLE 17 The racemic 2-exo-amino-3,4-endo-dihydroxy-8- methoxy-7-oxabicyclo 4,3 ,0 nonane hydrochloride(350 mg; 1.46 mmols), and 250 mg (1.84 mmols) of crystalline sodium acetate are dissolved at 5C in 6 ml of 50 percent aqueous acetic acid. While stirring and cooling with an ice-water bath, 1.5 ml of a 3 normal sodium nitrite solution are added to the resulting solution in an argon atmosphere within 40 minutes. After a total of minutes, the reaction mixture is neutralised with a suspension of 6 g of sodium hydrogen carbonate in 12 ml of water and extracted repeatedly with methylene chloride. The combined extracts are dried with sodium sulphate and the solvent is then distilled off in vacuo. The oily residue is the racemic 6- exo-formyl-3-methoxy-2-oxabicyclo[ 3 ,3 ,0] octan7- endo-ol, consisting of the compound of the formula From the 6S-2-exo-amino-3,4-endo-dihydroxy-8- methoxy-7-oxabicyclo[4,3 ,0 ]nonane hydrochloride there is obtained in analogous mannerthe lS-6-exoformyl-3-methoxy-2-oxabicyclo[3,3,0]octan-7-endool. The product is instable and is used at once.

EXAMPLE 179.

A solution of 25 mg (0.123 mmols) of the racemic 2-exo-amin0-3,4-endo-dihydroxy-8-methoxy-7- oxabicyclo[4,3,0] nonane in 5 ml of dry ethylene glycol dimethyl ether is treated at C with 120 mg of potasoxo-transl -octenyl )-2- oxabic yclo[3,3,0]octan-7-endo-ol is purified by preparative thin layer chromatography on silica gel with ethyl acetate as eluant. (Oil, which congrats to a crys- 5 talline solid on standing at 20, m.p. 8.5-9.5C).

In analogous manner there is obtained from the lS-6- exo-3-methoxy-2-oxabicyclo[ 3 ,3,0 ]octan-7-endo-ol the lS-3-methoxy-6-exo-( 3-oxo-transl -octenyl )-2- oxabicyclo[3,3,0]octan7-endo-ol; m.p. l l.5l 3C sium acetate while stirring, and dinitrogen tetroxide is 0 [01],, -69i1 (c= 1 percent in chloroform).

passed into the solution slowly over the course of 10 minutes. Excess dinitrogen tetroxide is then removed by scavenging with nitrogen, the solution is treated with 10 ml of water and 1 ml of saturated sodium carbonate solution and extracted with methylene chloride. The organic extract is dried over sodium sulphate and then evaporated.

The residue is the racemic 6exo-formyl-3-methoxy- 2-oxabicyclo [3,3,0]octan-7-endo-ol, which consists of EXAMPLE l9 A solution of 50 mg (0.177 mmols) of the racemic 3-methoxy-6-exo-( 3-oxo-transl-octenyl )-2- oxabicyclo[3,3,0]octan-7-endo-ol in 9 ml of methanol is treated at 0C while stirring with a solution of 338 mg (8.95 mmols) of sodium borohydride in 3 ml of water. The solution is stirred for 17 minutes at 0C, then poured on 150 ml of water. The resulting solution is exthe compound of the formula IXa and its optical anit- 2o tracted 3 times with ml of chloroform on each occapode.

EXAMPLE 18 OCH and its optical antipode is a yellow oil, which in the infrared zone has absorption maxima at 2.80; 2.90; 5.92; 5.98; 6.15;; and in the ultraviolet zone at 230mg. The melting point of its 7-endo-(3,5-dinitrobenzoyloxy) derivative (obtained from the above product with 3.5- dinitrobenzoyl chloride and pyridine) is 73-75,5C.

EXAMPLE 18a A solution of 550 mg (2.96 mmols) of the freshly manufactured racemic 6-exo-formyl-3-methoxy-2- oxabicyclo[3,3,0]octan-7-endo-ol in 18 ml of dry ethylene glycol dimethyl ether is treated with 1.39 g (4.4 mmols) of 1-tributylphosphoranylidene-Z-heptanone (b.p. C at 0.001 Torr, (S.:N.Finch and J.J.Fitt- .Tetr.Letters 1969 4639). The resulting solution is stirred under nitrogen for 2 hours at 50C and for 12 hours at room temperature, then concentrated in vacuo. The residue, the racemic 3-methoxy-6-exo-(3- sion, the combined extracts are dried over magnesium sulphate, evaporated, and the residue is dried for 1 hour in vacuo at 25C and 0.1 Torr. The residual oil is separated into two fractions by preparative thin layer chromatography on silica gel with ethyl acetate as eluant. The less polar fraction consists of the racemic 3- methoxy6-exo-( 3R-hydroxy-trans- 1 -octenyl )-2- oxabicyclo[3,3,0]octan-7-endo-ol, consisting of the compound of the formula and its optical antipode (R; on silica gel with ethyl acetate as eluant 0.31; m.p. of its bis-p-nitrobenzoyloxy derivative, obtained from the above product with p- 5 nitrobenzoyl chloride and pyridine, is 72-76C); and

the more polar one consists of the racemic 3-methoxy- 6-exo-( 3S-hydroxy-trans- 1 octeny1)-2- oxabicyclo[3,3,01octan-7-endo-ol which consists of the compound of the formula exo-( 3S-hydroxy-transl -octeny] )-2- oxabicyclo[3,3,0]octan-7-endo-ol; oil [a],, 72il (C 1 percent in chloroform), and the 1S-3-methoxy- 6-exo-(3R-hydroxy-transl-octenyl-)-2- oxabicyclo[3,3,0]octan-7-endo-ol. m.p. 5057C, [11],, 88:1 (c 1 percent in chloroform).

The 3-methoxy-6-exo-(3R-hydroxy-trans-1-octenyl) 2-oxabicyclo[3,3,0]octan-7-endo-ol which occurs as by-product can be led back into the process as follows:

A solution of 50 mg of the racemic 3-methoxy-6-exo- (3R-hydroxy-transl -octenyl )-2-oxabicyclo[ 3 ,3,0]octan-7-endool in 0.78 ml of methylene chloride is stirred in a nitrogen atmosphere for 17 hours with 782 mg of active precipitated manganese dioxide (Merck, Darmstadt). The mixture is then filtered through diatomaceous earth and evaporated. The residue is the racemic 3-methoxy-6-exo-( 3-oxo-transl -octenyl )-2- oxabicyclo[3,3,0]octan-7-endo-ol.

I claim:

1. A compound of the formula Vlll 2 (VIII) HO". "-oH wherein Z4 represents a member of a group consisting of a free hydroxyl group, a hydroxyl group etherified by a lower alkanol, a lower alkanol containing halogen or phenyl, a lower alkanol, in which the methylene group in the a-position is replaced by oxygen, a cycloalkanol with 5 to 7 carbon atoms, a cycloalkanol with 5 to 7 carbon atoms in which the methylene group in the a-position is replaced by oxygen, or by a tri-lower alkyl-silyl group, and a hydroxy] group esterified with a lower alkanecarboxylic acid, a halo-substituted lower 4. An optically active compound of the formula Vlll according to claim 1, wherein Z is a lower alk o xy group, and acid addition salts thereof. 5. The racemate of a compound of the formula Vlll according to claim 1, wherein Z. is a lower alkoxy group, and acid addition salts thereof.

6. The optically active compound of the formula Vlll,

according to claim 1, wherein Z is the methoxy group, and acid addition salts thereof.

7. The racemate of a compound of the formula Vlll according to claim 1, wherein Z, is the methoxy group,.

and acid addition salts thereof. 

1. A COMPOUND OF THE FORMULA VIII
 2. An optically active compound of the formula VIII according to claim 1, wherein Z4 represents a free, etherified or esterified hydroxy group, and the acid addition salts thereof.
 3. The racemate of a compound of the formula VIII according to claim 1, wherein Z4 represents a free, etherified or esterified hydroxy group, and acid addition salts thereof.
 4. An optically active compound of the formula VIII according to claim 1, wherein Z4 is a lower alkoxy group, and acid addition salts thereof.
 5. The racemate of a compound of the formula VIII according to claim 1, wherein Z4 is a lower alkoxy group, and acid addition salts thereof.
 6. The optically active compound of the formula VIII according to claim 1, wherein Z4 is the methoxy group, and acid addition salts thereof.
 7. The racemate of a compound of the formula VIII according to claim 1, wherein Z4 is the methoxy group, and acid addition salts thereof. 